Individual humans and animals vary widely in their susceptibility to drug dependence. Uncovering the substrates of these differences will provide important insights into the biology of drug addiction and will facilitate the development of more effective preventive and treatment strategies for this devastating illness. Epigenetic processes can greatly increase the complexity of genomic responses by allowing fine-tuning of the genome. Increasing evidence suggests that epigenetic processes contribute to complex diseases, including mental disorders. One of the recently appreciated epigenetic mechanisms is RNA editing. To date, RNA editing has not been examined in relation to the propensity for drug addiction; we propose to do so in the present application. Activation of the serotonin 2C receptors (5-HT2CRs) attenuates, and inhibition of 5-HT2CRs potentiates dopamine release as well as drug-seeking behavior of a variety of addictive drugs. The mRNA editing of the 5-HT2CR may give rise to up to 24 distinct isoforms which vary in their functional activity. We, therefore, propose as the overarching hypothesis of this application that that variations in an individual's repertoire of the 5-HT2CR isoforms and/or in the mRNA expression level of the receptor may underlie phenotypic differences in responsivity to drugs of abuse and predisposition to addiction. It has been established that rats with a high locomotor response to a novel environment (high responders, HRs) exhibit enhanced drug-related behaviors compared with rats with a low response (LRs). We will employ animals that express the extremes of these phenotypes in order to relate 5-HT2CR mRNA editing and expression in the ventral tegmental area (VTA) and prefrontal cortex (RFC) to vulnerability to drug abuse. The 5-HT2CR editing will be determined by sequence analysis of multiple clones, and its mRNA expression will be measured by real time PCR. We will test the hypotheses that 5-HT2CR mRNA editing will be enhanced, while its mRNA expression will be lower, in the VTA and PFC of HRs compared to LRs. Because the use of drugs to screen the animals for differences in drug-seeking behavior might alter receptor expression and/or editing, employing the HRs/LRs model brings about an enormous advantage by avoiding the confounding effects of drugs on the results of the study. [unreadable] [unreadable] [unreadable]